The enormous phenotypic diversity of neural cell types implies a corresponding complexity of gene-specific transcription factor combinations required to regulate thousands of genes in the appropriate stage and cell type-specific manner (He, X., and Rosenfeld, M. G., "Mechanisms of complex transcriptional regulation: implications for brain development" Neuron 7:183-196, 1991; Mandel, G., and McKinnon, D, "Molecular basis of neural-specific gene expression" Annu. Rev. Neurosci. 16:323-345, 1993; Struhl, K., "Mechanisms for diversity in gene expression patterns" Neuron 7:177-181, 1991). Indeed, several members of different transcription factor classes, such as homeodomain, zinc-finger and basic helix-loop-helix proteins, function to regulate neural cell-type identity in specific regions of both the vertebrate and invertebrate nervous systems. Many of these genes are expressed early in neural development, which suggests they play a critical role in neurogenesis and neuronal patterning (Tanabe, Y., and Jessell, T. M., "Diversity and pattern in the developing spinal cord" Science 274:1115-1124, 1996). However, an understanding of the functional interplay between different transcription factors and the neural genes they regulate is just beginning to emerge. Little is known about the identity and specific functions of transcription factors which operate particular differentiation programs involved in the appearance and maintenance of specific neural cell phenotypes.
The central serotonin (5-HT) neurotransmitter system consists of a relatively small population of morphologically diverse neurons whose cell bodies are present largely within the limits of the midbrain/hindbrain raphe nuclei and particular regions of the reticular formation (Steinbusch, H. W. M., Neuroscience 6:557-618, 1981). Although there are only about 20,000 serotonergic neurons in the rat brain the extensive axonal projection system arising from these neurons bears a tremendous number of collateral branches so that the 5-HT system densely innervates nearly all regions of the central nervous system (Halliday, G., Harding, A., and Paxinos, G. (1995) in The rat nervous system (Paxinos, G. ed), 2nd Ed., pp. 929-974, Academic Press, San Diego; Jacobs, B. L., and Azmitia, E. C., Physiological Reviews 72:165-220, 1992). Given its widespread distribution it is not surprising that 5-HT has been implicated in the control of numerous neural systems which mediate such functions as cognition, aggression, and perception (Heninger, G. R., Proc. Natl. Acad. Sci. USA 94:4823-4824, 1997). Abnormal function of the central 5-HT system has been implicated in several psychiatric maladies such as depression, anxiety, and eating disorders. The people afflicted by diseases caused or potentiated by abnormalities in the central serotonin 5-HT neurotransmitter system numbers in the millions. In this regard, this system is the target of several highly effective pharmacological agents that are used widely to treat these conditions. However, the current pharmacological agents may possess cross reactivity with other components of the central nervous system resulting in unwanted or debilitating side effects. Additionally, despite the clear importance of the central serotonin 5-HT system in a wide range of CNS processes and clinical disorders little is known about the genetic mechanisms which control the specification and differentiation of serotonergic neurons.
What is needed are reagents and methods that can be utilized in the screening of pharmacological compounds that can be utilized in the treatment of neurological diseases involving the central serotonin (5-HT) neurotransmitter system.